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The alpha-1,3-galactosyltransferase knockout mouse. Implications for xenotransplantation
R G Tearle1, M J Tange, Z L Zannettino
1Department of Clinical Immunology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Transplantation
|January 15, 1996
Summary
Mice lacking the galactose alpha(1,3)-galactose epitope show reduced human antibody binding, confirming its role in xenograft rejection. This research supports developing pigs without this epitope for organ transplantation.
Area of Science:
- Immunology
- Transplantation Biology
- Genetics
Background:
- Hyperacute rejection of pig-to-man organ xenografts is mediated by human anti-pig xenoantibodies.
- The galactose alpha(1,3)-galactose epitope is the primary target of these xenoantibodies.
- This epitope is synthesized by alpha(1,3)-galactosyltransferase, absent in humans but present in pigs.
Purpose of the Study:
- To investigate the role of the galactose alpha(1,3)-galactose epitope in human xenoreactivity.
- To generate a mouse model lacking this major xenoantigen for experimental studies.
Main Methods:
- Gene targeting to inactivate the alpha(1,3)-galactosyltransferase gene in mice.
- Assessment of xenoantibody binding from human serum to mouse cells and tissues.
- Evaluation of human complement activation on cells from genetically modified mice.
Main Results:
- Mice lacking the alpha(1,3)-galactosyltransferase gene were viable with normal organs, though cataracts developed.
- Significantly reduced binding of human xenoantibodies to cells and tissues of knockout mice.
- Decreased activation of human complement on cells from mice lacking the target epitope.
Conclusions:
- The galactose alpha(1,3)-galactose epitope is crucial for human xenoreactivity.
- These mice serve as a valuable model for studying xenotransplantation barriers.
- The findings support efforts to create pigs lacking this epitope for xenotransplantation.